A Mouse Model of Amyloid β Oligomers: Their Contribution to Synaptic Alteration, Abnormal Tau Phosphorylation, Glial Activation, and Neuronal Loss In Vivo
A Mouse Model of Amyloid β Oligomers: Their Contribution to Synaptic Alteration, Abnormal Tau Phosphorylation, Glial Activation, and Neuronal Loss In Vivo
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DOI：
10.1523/jneurosci.5825-09.2010
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发表时间：
2010-04-07
影响因子：
5.3
通讯作者：
Mori, Hiroshi
中科院分区：
文献类型：
--
作者：
Tomiyama, Takami;Matsuyama, Shogo;Mori, Hiroshi
虽然淀粉样蛋白β（A β）寡聚体被认为是导致阿尔茨海默病（AD）中突触和认知功能障碍的原因，但其对AD的其他病理特征的贡献仍不清楚。为了解决后者，我们产生了表达E693 Delta突变的APP转基因小鼠，E693 Delta突变通过增强A β寡聚化而不发生fifilization来引起AD。这些小鼠从8个月开始就表现出神经元内A β寡聚体的年龄依赖性积累，但即使在24个月时也没有细胞外淀粉样蛋白沉积。海马突触可塑性和记忆在8个月时受损，此时突触前标记物突触素开始减少。此外，我们在8个月时检测到异常tau磷酸化，12个月时检测到小胶质细胞活化，18个月时检测到星形胶质细胞活化，24个月时检测到神经元丢失。这些发现表明，A β寡聚体不仅引起突触改变，而且还引起AD病理学的其他特征，并且这些小鼠是在不存在淀粉样斑块的情况下A β寡聚体诱导的病理学的有用模型。
Although amyloid beta(A beta) oligomers are presumed to cause synaptic and cognitive dysfunction in Alzheimer's disease (AD), their contribution to other pathological features ofADremains unclear. To address the latter, we generated APP transgenic mice expressing the E693 Delta mutation, which causes AD by enhanced A beta oligomerization without fibrillization. The mice displayed age-dependent accumulation of intraneuronal A beta oligomers from 8 months but no extracellular amyloid deposits even at 24 months. Hippocampal synaptic plasticity and memory were impaired at 8 months, at which time the presynaptic marker synaptophysin began to decrease. Furthermore, we detected abnormal tau phosphorylation from 8 months, microglial activation from 12 months, astrocyte activation from 18 months, and neuronal loss at 24 months. These findings suggest that A beta oligomers cause not only synaptic alteration but also other features of AD pathology and that these mice are A useful model of A beta oligomer-induced pathology in the absence of amyloid plaques.